DESCRIPTION: (Applicant's Abstract) Research into the central nervous system mechanisms of drug reinforcement has centered on a particular population of dopamine neurons located in the ventral midbrain. Research with animal models has established that these mesolimbic dopamine cells play a major role in drug-seeking behavior and has led on occasion to testing of dopaminergic agents as "medications" to assist in reducing drug abuse disorders. While the central role of dopamine systems in drug reinforcement has become evident, the ubiquitous involvement of dopamine systems in motivated behavior and motor functions speaks to the need for the development of highly selective interventions in the dopamine system if medications specific for drug-use disorders are to be obtained. To support a strategic approach to the testing of pharmacotherapeutic agents for potential benefit in drug abuse treatment, additional knowledge is essential. The approach to be taken in this research is to discover other neuronal systems which physiologically regulate mesolimbic dopamine neurons. In this case, the promise is that highly selective interventions might be crafted which would mimic the action of the normal physiological inputs to those dopamine cells which themselves are critical in initiating and maintaining drug-taking behavior. This preclinical research will employ primarily the techniques of behavioral pharmacology and neuroscience to understand how two particular neurochemical systems can control the dopamine processes which mediate cocaine and nicotine addiction. One system of interest is cholinergic. Previous studies have demonstrated that nicotine activates the mesolimbic dopamine projection neurons as do other drugs such as cocaine, but does so by targeting nicotinic receptors in the vicinity of the dopamine cell bodies. This site of action for nicotine implicates known cholinergic inputs in nicotine reinforcement, and generally in the regulation of mesolimbic dopaminergic cells. Therefore, one strategy in this research is to examine the influence of the cholinergic system on drug reinforcement, using animal models in which the subjects self-administer nicotine or cocaine. Secondly, it is apparent that cocaine reinforcement can be reduced by treatment with opiate antagonists administered systemically, and recent research has shown that mu-type opiate receptors in the ventral tegmental area are critical in this effect. The second strategy in this research is, then, to investigate the mechanisms by which opiates regulate the mesolimbic dopamine systems in cocaine reinforcement.